Cellular proliferation and growth are two mechanisms leading to vascular remodelling commonly observed in vascular muscular cells in response to diverse pathological stimuli. Excessive smooth muscle cells proliferation is a fundamental process that contributes to the injury response in major arterial vessels. Such process is involved in numerous vascular disorders including atherosclerosis, post-angioplasty restenosis, pulmonary arterial hypertension and vein-graft disease (Dzau V J and al., 2002; Novak K., 1998). Identifying modifiers of vascular smooth muscle cell (VSMC) proliferation is thus a major focus of research in cardiovascular biology and medicine.
Stereotypical pattern of changes in gene expression that include the re-expression of fetal genes are observed. Such differences are controlled by particular underlying signalling pathways. Advances in the description of signalling pathways involved in pathological vascular smooth muscle cells proliferation have pointed on regulatory pathways controlled by cyclic nucleotides. Cyclic nucleotides, namely adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP), are key second messengers acting as negative regulators of smooth muscle cells proliferation. The synthesis of cyclic AMP or cyclic GMP in cells is catalyzed by the adenylyl or guanylyl cyclase enzymes, respectively (McDonald & Murad, 1996; Sunahara and al., 1996). The elevation of intracellular cAMP and cGMP concentrations by cAMP or cGMP analogues, both independently inhibit rabbit vascular smooth muscle cell proliferation. (Assender J W. and al, 1992). Reexpression of constitutively active Protein kinase G (PKG) (or wild type PKG with cGMP stimulation) inhibits VSMC migration, enhances apoptosis, reduces proliferation, and decreases neointima formation after vascular injury. (Boerth N J and al,. 1997; Sinnaeve P and al. 2002).
Following these results, focus has been made on process involved in cyclic nucleotides elimination. These cyclic nucleotides can be degraded by specific members of the phosphodiesterase (PDE) superfamily that are responsible for the hydrolysis of intracellular cAMP and cGMP. (Rybalkin and al., 2003)
Recently, Chen et al (JBC; 2001) has reported that the cAMP and the cGMP can also be transported by active efflux transporters, namely the multidrug resistance proteins (MRP) MRP4 and MRP5, encoded by the ATP-Binding Cassette transporters class C (ABCC) 4 and ABCC5 genes respectively. Among this transporter family, MRP4 and MRP5 shows high affinity for cAMP and cGMP. To date, however, the physiological function of these proteins remains unclear. Recently, MRP4 and MRP5 were identified as ATP-dependent export pumps for cyclic nucleotides (Jedlitschky and al., 2000; Chen and al., 2001) and it has been shown that MRP4 and MRP5 are expressed in the porcine coronary and pulmonary arteries (Mitani et al; 2003).